Project Summary The type I interferon (IFN) cytokine family promotes the development of systemic lupus erythematosus (SLE) and is made by many different cells in response to DNA and RNA. Whereas many cells of the immune system make type I interferon, plasmacytoid dendritic cells (pDC) are a specialized cell type that can produce large quantities of these cytokines in response to nucleic acids in immune complexes, which are abundant in SLE. pDC have been implicated as important type I interferon producing cells in SLE, both in humans and in mouse models. We have made the novel discovery that the signaling adapter BCAP, which is highly expressed in pDC, is required for type I interferon production from these cells. Additionally, deficiency in BCAP in a mouse model of lupus-like disease greatly ameliorates disease. Therefore, BCAP is a potential therapeutic target in SLE to reduce pDC interferon-alpha production. In this proposal, we further examine the function of BCAP in pDC interferon-alpha production and in lupus-like disease. We will explore this idea in two aims: 1) To determine the mechanism by which BCAP regulates plasmacytoid DC type I IFN production, and 2) To determine if BCAP expression in pDC promotes lupus-like disease. Together, these experiments will define a new regulatory mechanism for pDC type I IFN production in vitro and in vivo. BCAP has not previously been implicated in pDC function or in SLE pathogenesis, therefore our proposal tests novel hypotheses focused on determining how BCAP functions in pDC and whether BCAP may be a therapeutic target in SLE.